This invention relates to the synthesis of alkali metal salts of methionine and its analogs and, more particularly, to an improved process for the synthesis of such compounds in high yields without the necessity of using acrolein or hydrogen cyanide as precursors.
The hydroxy analog of methionine, i.e., 2-hydroxy-4-methylthiobutyric acid, is widely used as an animal feed supplement. According to a conventional process for the preparation of 2-hydroxy-4-methylthiobutyric acid (HMBA), 2-hydroxy-4-methylthiobutyronitrile (HMBN) is hydrolyzed with a mineral acid. As described for example in Blake et al. U.S. Pat. No. 2,745,745, HMBN is typically prepared by reacting 3-methylthiopropionaldehyde with hydrogen cyanide. The 3-methylthiopropionaldehydyde intermediate is in turn prepared by condensation of acrolein and methyl mercaptan. Thus, in the commercial manufacture of HMBA, acrolein and hydrogen cyanide have been essential starting materials.
The toxicity of hydrogen cyanide is well known. Acrolein is also toxic, and both materials are flammable as well. Accordingly, the shipping and handling of these raw materials is costly.
Accordingly, there has been a long standing need for commercially feasible processes for the manufacture of 2-hydroxy-4-methylthiobutyric acid and related compounds without the necessity of using acrolein and hydrogen cyanide as precursor materials.
Plieninger, "Cleavage of gamma-Butyrolactone and alpha-Amino-butyrolactone with Sodium Methylmercaptide or Selenide. A Synthesis of Methionine.", Chem. Ber., vol. 83, pages 265-268 (1950), Chem. Abstracts, 44:9919b describes the reaction of unsubstituted butyrolactone and sodium methylmercaptide in a toluene medium. The reference also describes the formation of methionine by reaction of sodium methylmercaptide with alpha-aminobutyrolactone in toluene. Further described in the reference is a reaction of alpha-amino-butyrolactone with sodium methyl selenide. Neutralization with acetic acid converts the alkali metal salt products of these reactions to the corresponding free acids. Plieninger further describes the preparation of sodium methylmercaptide by passing methyl mercaptan into methanol containing metallic sodium, concentrating the resultant mixture by evaporation of solvent, adding toluene, and distilling off solvent until the boiling point of toluene is reached. Alternatively, metallic sodium is added to a solution of methyl mercaptan and liquid ammonia, following which toluene is added and ammonia evaporated to precipitate an amorphous sodium methylmercaptide.
British Pat. No. 651,165 also describes the preparation of methionine by the reaction of alpha-aminobutyrolactone with sodium methyl mercaptide. The examples in this patent describe both a violent reaction obtained by addition of alpha-amino-butyrolactone (neat) to dry sodium methylmercaptide (neat), and a suspension reaction in xylene. Reaction is carried out at a temperature of 150-200.degree. C. The sodium salt of methionine obtained from the reaction is acidified with acetic acid to pH 7. As prior art, the British patent also describes the preparation of methionine by benzoylation of alpha-aminobutyrolactone, conversion of the N-benzoyl compound to a gamma-chloro-alpha-benzoylaminobutyric acid ester by treatment with alcoholic hydrochloric acid, and reaction of the ester with sodium methylmercaptide to produce N-benzoyl methionine. The benzoyl blocking group is removed by hydrolysis to produce methionine.
German Pat. No. 816,544 (Chem. Abstracts, vol. 47: 2200e) describes a process for preparing gammaalkylthio or -seleno fatty acids or their amino derivatives by reaction of the corresponding alkali metal alkylmercaptide or -selenide with gamma-lactones at temperatures in the range of 100-200.degree. C. in the presence of an inert solvent such as benzene or toluene. The examples of this patent illustrate reaction of sodium methylmercaptide with gamma-butyrolactone in a toluene suspension. Further examples show use of the same toluene medium for the preparation of methionine from sodium methylmercaptide and alpha-amino-gamma-butyrolactone.
Chem. Abstracts 51:2853c describes still another process in which a toluene medium is used for reaction of sodium methylmercaptide with a gamma-butyrolactone. In this case the lactone substrate is alphabenzoylamino-gamma-butyrolactone and the benzoyl protecting group is removed by neutralization with sodium carbonate to produce D,L-methionine. While the methods described in Pleininger, British Pat. No. 651,165, German Pat. No. 816,544, and CA 51:2835c have been shown to be effective for the preparation for alkylthiobutyric acid salts, the yields obtainable by reaction in inert solvents such as toluene and xylene have not been commercially attractive.
Aries French Pat. No. 2,271,207, describes a process for the preparation of methionine in which 3-methylthiopropylisonitrile is reacted with a dialkyl carbonate in the presence of sodium hydride, and the product of this reaction is hydrolyzed to methionine. Reaction between the 3-methylthiopropylisonitrile and dialkyl arbonate is carried out in dimethylformamide, after which that solvent is removed by evaporation and the residue washed with pentane and dissolved in methanol. Hydrolysis is carried out by addition of hydrochloric acid, and methionine is recovered by evaporating the methanol and HCl, washing the residue with isopropyl ether, adding sodium hydroxide to pH 6, and crystallizing the product from methanol. The 3-methylthiopropylisonitrile starting material is said to be prepared readily from methylthiopropylamine in accordance with the description in Tetrahedron Letters, 1972, p. 1637.
Jaworski U.S. Pat. No. 3,671,212 describes the preparation of a salt of 2-hydroxy-4-methylthiobutyric acid by hydrolysis of HMBN. HMBN is prepared by condensation of methyl mercaptan with 2-hydroxy-4-chlorobutyronitrile. The reference does not disclose the method of preparation of the 2-hydroxy-4-chlorobutyronitrile.